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MCP-1 (monocyte chemoattractant protein-1) is a proinflammatory cytokine involved in chemotaxis of monocytes. In several diseases, such as acute coronary syndromes and heart failure, elevated MCP-1 levels have been associated with poor outcomes. Little is known about MCP-1 in cirrhosis.To investigate the relationship between MCP-1 and outcome in decompensated cirrhosis.Prospective study of 218 patients discharged from hospital after an admission for complications of cirrhosis. Urine and plasma levels of MCP-1 and other urine proinflammatroy biomarkers: osteopontin(OPN), trefoil-factor3 and liver-fatty-acid-binding protein were measured at admission. Urine non-inflammatory mediators cystatin-C, β2microglobulin and albumin were measured as control biomarkers. The relationship between these biomarkers and the 3-month hospital readmission, complications of cirrhosis, and mortality were assessed.69 patients(32%) had at least one readmission during the 3-month period of follow-up and 30 patients died(14%). Urine MCP-1 and OPN levels, were associated with 3-month probability of readmission (0.85 (0.27-2.1) and 2003 (705-4586) ug/g creat vs 0.47 (0.2-1.1) and 1188 (512-2958) ug/g creat, in patients with and without readmission, respectively; p

INTRODUCTION:The aim of this study was to determine prognostic factors for the risk of new vascular events during the first 6 months after acute myocardial infarction (AMI) or atherothrombotic stroke (AS). We were interested in the prognostic role of endothelial progenitor cells (EPC) and circulating endothelial cells (CEC). METHODS:Between February 2009 and July 2012, 100 AMI and 50 AS patients were consecutively studied in three Spanish centres. Patients with previously documented coronary artery disease or ischemic strokes were excluded. Samples were collected within 24h of onset of symptoms. EPC and CEC were studied using flow cytometry and categorized by quartiles. Patients were followed for up to 6 months. NVE was defined as new acute coronary syndrome, transient ischemic attack (TIA), stroke, or any hospitalization or death from cardiovascular causes. The variables included in the analysis included: vascular risk factors, carotid intima-media thickness (IMT), atherosclerotic burden and basal EPC and CEC count. Multivariate survival analysis was performed using Cox regression analysis. RESULTS:During follow-up, 19 patients (12.66%) had a new vascular event (5 strokes; 3 TIAs; 4 AMI; 6 hospitalizations; 1 death). Vascular events were associated with age (P = 0.039), carotid IMT≥0.9 (P = 0.044), and EPC count (P = 0.041) in the univariate analysis. Multivariate Cox regression analysis showed an independent association with EPC in the lowest quartile (HR: 10.33, 95%CI (1.22-87.34), P = 0.032] and IMT≥0.9 [HR: 4.12, 95%CI (1.21-13.95), P = 0.023]. CONCLUSIONS:Basal EPC and IMT≥0.9 can predict future vascular events in patients with AMI and AS, but CEC count does not affect cardiovascular risk.

Background and aimsStigmatization is a well-documented problem of some diseases. Perceived stigma is common in alcohol-related liver disease and hepatitis C, but little information exists on stigma in patients with non-alcoholic fatty liver disease (NAFLD). Aim of the study was to investigate frequency and characteristics of perceived stigma among patients with NAFLD.MethodsOne-hundred and ninety-seven patients seen at the liver clinic were included: a study group of 144 patients with NAFLD, 50 with cirrhosis (34 compensated, 16 decompensated), and a control group of 53 patients with alcohol-related cirrhosis. Demographic, clinical, and laboratory data were collected. Quality-of-life was assessed by chronic liver disease questionnaire (CLDQ). Perceived stigma was assessed using a specific questionnaire for patients with liver diseases categorized in 4 domains: stereotypes, discrimination, shame, and social isolation.ResultsPerceived stigma was common in patients with NAFLD (99 patients, 69%) and affected all 4 domains assessed. The frequency was slightly higher, yet not significant, in patients with NAFLD cirrhosis vs those without (72% vs 67%, respectively; p = 0.576). In patients without cirrhosis perceived stigma was unrelated to stage of disease, since frequency was similar in patients with no or mild fibrosis compared to those with moderate/severe fibrosis (66% vs 68%, respectively). There were no differences in perceived stigma between patients with compensated cirrhosis and these with decompensated cirrhosis. Among patients with cirrhosis, stigmatization was more common in alcohol-related vs NAFLD-cirrhosis, yet differences were only significant in two domains. In patients with NAFLD, perceived stigma correlated with poor quality-of-life, but not with demographic or clinical variables.ConclusionsPerceived stigmatization is common among patients with NAFLD independently of disease stage, is associated with impaired quality-of-life, and may be responsible for stereotypes, discrimination, shame, and social isolation, which may affect human and social rights of affected patients.

BACKGROUND:Primary care is the ideal setting for early identification of patients with non-alcoholic fatty liver disease (NAFLD). NAFLD is a potentially progressive disease that may lead to cirrhosis and liver cancer but is frequently underrecognized because subjects at risk are often not evaluated. Controlled attenuation parameter (CAP) is a reliable method for non-invasive quantification of liver fat. It has the advantage of simultaneous measurement of liver stiffness (LS), an estimate of liver fibrosis. There is no information on CAP in subjects with risk factors from primary care. AIM:To investigate the prevalence of hepatic steatosis, as estimated by CAP, in subjects from the community with metabolic risk factors and correlate findings with clinical and biochemical characteristics and LS. PATIENTS AND METHODS:Population-based study of 215 subjects with metabolic risk factors without known liver disease identified randomly from a primary care center. A control group of 80 subjects matched by age and sex without metabolic risk factors was also studied. CAP and LS were assessed using Fibroscan. RESULTS:Subjects with risk factors had CAP values higher than those of control group (268±64 vs 243±49dB/m,p 280dB/m) in subjects with risk factors was 43%. In multivariate analysis, fatty liver index (FLI) and HOMA were independent predictive factors of severe steatosis. There was a direct correlation between CAP and FLI values (r = 0.52,p

Biomarkers are potentially useful in assessment of outcomes in patients with cirrhosis, but information is very limited. Given the large number of biomarkers, adequate choice of which biomarker(s) to investigate first is important.Analysis of potential usefulness of a panel of urinary biomarkers in outcome assessment in cirrhosis.Fifty-five patients with acute decompensation of cirrhosis were studied: 39 had Acute Kidney Injury (AKI) (Prerenal 12, type-1 HRS (hepatorenal syndrome) 15 and Acute Tubular Necrosis (ATN) 12) and 16 acute decompensation without AKI. Thirty-four patients had Acute-on-chronic liver failure (ACLF). A panel of 12 urinary biomarkers was assessed, using a multiplex assay, for their relationship with ATN, ACLF and mortality.Biomarker with best accuracy for ATN diagnosis was NGAL (neutrophil-gelatinase associated lipocalin): 36 [26-125], 104 [58-208] and 1807 [494-3,716] μg/g creatinine in Prerenal-AKI, type-1 HRS and ATN, respectively; p

Chronic liver diseases are characterized by a sustained inflammatory response in which chemokines and chemokine-receptors orchestrate inflammatory cell recruitment. In this study we investigated the role of the chemokine receptor CCR6 in acute and chronic liver injury. In the absence of liver injury Ccr6-/- mice presented a higher number of hepatic macrophages and increased expression of pro-inflammatory cytokines and M1 markers Tnf-α, Il6 and Mcp1. Inflammation and cell recruitment were increased after carbon tetrachloride-induced acute liver injury in Ccr6-/- mice. Moreover, chronic liver injury by carbon tetrachloride in Ccr6-/- mice was associated with enhanced inflammation and fibrosis, altered macrophage recruitment, enhanced CD4+ cells and a reduction in Th17 (CD4+IL17+) and mature dendritic (MHCII+CD11c+) cells recruitment. Clodronate depletion of macrophages in Ccr6-/- mice resulted in a reduction of hepatic pro-inflammatory and pro-fibrogenic markers in the absence and after liver injury. Finally, increased CCR6 hepatic expression in patients with alcoholic hepatitis was found to correlate with liver expression of CCL20 and severity of liver disease. In conclusion, CCR6 deficiency affects hepatic inflammatory cell recruitment resulting in the promotion of hepatic inflammation and fibrosis.

Background and Aims: Stigmatization is a well-documented problem of some diseases. Perceived stigma is common in alcohol-related liver disease and hepatitis C, but little information exists on stigma in patients with non-alcoholic fatty liver disease (NAFLD). Aim of the study was to investigate frequency and characteristics of perceived stigma among patients with NAFLD., Methods: One-hundred and ninety-seven patients seen at the liver clinic were included: a study group of 144 patients with NAFLD, 50 with cirrhosis (34 compensated, 16 decompensated), and a control group of 53 patients with alcohol-related cirrhosis. Demographic, clinical, and laboratory data were collected. Quality-of-life was assessed by chronic liver disease questionnaire (CLDQ). Perceived stigma was assessed using a specific questionnaire for patients with liver diseases categorized in 4 domains: stereotypes, discrimination, shame, and social isolation., Results: Perceived stigma was common in patients with NAFLD (99 patients, 69%) and affected all 4 domains assessed. The frequency was slightly higher, yet not significant, in patients with NAFLD cirrhosis vs those without (72% vs 67%, respectively; p = 0.576). In patients without cirrhosis perceived stigma was unrelated to stage of disease, since frequency was similar in patients with no or mild fibrosis compared to those with moderate/severe fibrosis (66% vs 68%, respectively). There were no differences in perceived stigma between patients with compensated cirrhosis and these with decompensated cirrhosis. Among patients with cirrhosis, stigmatization was more common in alcohol-related vs NAFLD-cirrhosis, yet differences were only significant in two domains. In patients with NAFLD, perceived stigma correlated with poor quality-of-life, but not with demographic or clinical variables., Conclusions: Perceived stigmatization is common among patients with NAFLD independently of disease stage, is associated with impaired quality-of-life, and may be responsible for stereotypes, discrimination, shame, and social isolation, which may affect human and social rights of affected patients., Competing Interests: Disclosures: PG reports Investigator Research grant and Advisory Board for Grífols, Investigator Research grant and Advisory Board for Gilead, Investigator Research grant from Mallinckrodt, Advisory Board for Promethera, Advisory Board for Martin-Pharmaceuticals, grants from Ferring-Pharmaceuticals, grants and Advisory Board work from Sequana, all outside the submitted work. The other authors have declared no conflict of interests.

Background: Primary care is the ideal setting for early identification of patients with non-alcoholic fatty liver disease (NAFLD). NAFLD is a potentially progressive disease that may lead to cirrhosis and liver cancer but is frequently underrecognized because subjects at risk are often not evaluated. Controlled attenuation parameter (CAP) is a reliable method for non-invasive quantification of liver fat. It has the advantage of simultaneous measurement of liver stiffness (LS), an estimate of liver fibrosis. There is no information on CAP in subjects with risk factors from primary care., Aim: To investigate the prevalence of hepatic steatosis, as estimated by CAP, in subjects from the community with metabolic risk factors and correlate findings with clinical and biochemical characteristics and LS., Patients and Methods: Population-based study of 215 subjects with metabolic risk factors without known liver disease identified randomly from a primary care center. A control group of 80 subjects matched by age and sex without metabolic risk factors was also studied. CAP and LS were assessed using Fibroscan., Results: Subjects with risk factors had CAP values higher than those of control group (268±64 vs 243±49dB/m,p<0.001). Prevalence of severe steatosis (CAP> 280dB/m) in subjects with risk factors was 43%. In multivariate analysis, fatty liver index (FLI) and HOMA were independent predictive factors of severe steatosis. There was a direct correlation between CAP and FLI values (r = 0.52,p<0.001). Interestingly, prevalence of increased LS was 12.6% in the risk group vs 0% in the control group (p<0.001). Increased LS occurred predominantly in subjects with high CAP values., Conclusions: A high proportion of subjects with metabolic risk factors seen in primary care have severe steatosis. FLI could be used as a surrogate of CAP. Increased LS was found in a significant proportion of subjects with risk factors but not in control subjects., Competing Interests: Pere Ginès declares he has received research funding from Grifols S.A, Ferring Pharmaceuticals, Sequana. He has consulted for Mallinckrodt, Intercept, Sequana, Ferring and Grifols. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials. No other authors have any competing interests.

Unlabelled: MCP-1 (monocyte chemoattractant protein-1) is a proinflammatory cytokine involved in chemotaxis of monocytes. In several diseases, such as acute coronary syndromes and heart failure, elevated MCP-1 levels have been associated with poor outcomes. Little is known about MCP-1 in cirrhosis., Aim: To investigate the relationship between MCP-1 and outcome in decompensated cirrhosis., Methods: Prospective study of 218 patients discharged from hospital after an admission for complications of cirrhosis. Urine and plasma levels of MCP-1 and other urine proinflammatroy biomarkers: osteopontin(OPN), trefoil-factor3 and liver-fatty-acid-binding protein were measured at admission. Urine non-inflammatory mediators cystatin-C, β2microglobulin and albumin were measured as control biomarkers. The relationship between these biomarkers and the 3-month hospital readmission, complications of cirrhosis, and mortality were assessed., Results: 69 patients(32%) had at least one readmission during the 3-month period of follow-up and 30 patients died(14%). Urine MCP-1 and OPN levels, were associated with 3-month probability of readmission (0.85 (0.27-2.1) and 2003 (705-4586) ug/g creat vs 0.47 (0.2-1.1) and 1188 (512-2958) ug/g creat, in patients with and without readmission, respectively; p<0.05; median (IQR)). Furthermore, urine levels of MCP-1 were significantly associated with mortality (1.01 (1-3.6) vs 0.5 (0.2-1.1) μg/g creat, in dead and alive patients at 3 months; p<0.05). Patients with higher levels of urine MCP-1 (above percentile 75th) had higher probability of development of hepatic encephalopathy, bacterial infections or AKI. Urine MCP-1 was an independent predictive factor of hospital readmission and combined end-point of readmission or dead at 3 months. Plasma levels of MCP-1 did not correlated with outcomes., Conclusion: Urine, but not plasma, MCP-1 levels are associated with hospital readmission, development of complications of cirrhosis, and mortality. These results suggest that in cirrhosis there is an inflammatory response that is associated with poor outcomes.

Chronic liver diseases are characterized by a sustained inflammatory response in which chemokines and chemokine-receptors orchestrate inflammatory cell recruitment. In this study we investigated the role of the chemokine receptor CCR6 in acute and chronic liver injury. In the absence of liver injury Ccr6-/- mice presented a higher number of hepatic macrophages and increased expression of pro-inflammatory cytokines and M1 markers Tnf-α, Il6 and Mcp1. Inflammation and cell recruitment were increased after carbon tetrachloride-induced acute liver injury in Ccr6-/- mice. Moreover, chronic liver injury by carbon tetrachloride in Ccr6-/- mice was associated with enhanced inflammation and fibrosis, altered macrophage recruitment, enhanced CD4+ cells and a reduction in Th17 (CD4+IL17+) and mature dendritic (MHCII+CD11c+) cells recruitment. Clodronate depletion of macrophages in Ccr6-/- mice resulted in a reduction of hepatic pro-inflammatory and pro-fibrogenic markers in the absence and after liver injury. Finally, increased CCR6 hepatic expression in patients with alcoholic hepatitis was found to correlate with liver expression of CCL20 and severity of liver disease. In conclusion, CCR6 deficiency affects hepatic inflammatory cell recruitment resulting in the promotion of hepatic inflammation and fibrosis.

Background: Biomarkers are potentially useful in assessment of outcomes in patients with cirrhosis, but information is very limited. Given the large number of biomarkers, adequate choice of which biomarker(s) to investigate first is important., Aim: Analysis of potential usefulness of a panel of urinary biomarkers in outcome assessment in cirrhosis., Patients and Methods: Fifty-five patients with acute decompensation of cirrhosis were studied: 39 had Acute Kidney Injury (AKI) (Prerenal 12, type-1 HRS (hepatorenal syndrome) 15 and Acute Tubular Necrosis (ATN) 12) and 16 acute decompensation without AKI. Thirty-four patients had Acute-on-chronic liver failure (ACLF). A panel of 12 urinary biomarkers was assessed, using a multiplex assay, for their relationship with ATN, ACLF and mortality., Results: Biomarker with best accuracy for ATN diagnosis was NGAL (neutrophil-gelatinase associated lipocalin): 36 [26-125], 104 [58-208] and 1807 [494-3,716] μg/g creatinine in Prerenal-AKI, type-1 HRS and ATN, respectively; p<0.0001 (AUROC 0.957). Other attractive biomarkers for ATN diagnosis were IL-18, albumin, trefoil-factor-3 (TFF-3) and glutathione-S-transferase-π (GST-π) Biomarkers with less accuracy for ATN AUCROC<0.8 were β2-microglobulin, calbindin, cystatin-C, clusterin and KIM-1 (kidney injury molecule-1). For ACLF, the biomarker with the best accuracy was NGAL (ACLF vs. No-ACLF: 165 [67-676] and 32 [19-40] μg/g creatinine; respectively; p<0.0001; AUROC 0.878). Interestingly, other biomarkers with high accuracy for ACLF were osteopontin, albumin, and TFF-3. Biomarkers with best accuracy for prognosis were those associated with ACLF., Conclusions: A number of biomarkers appear promising for differential diagnosis between ATN and other types of AKI. The most interesting biomarkers for ACLF and prognosis are NGAL, osteopontin, albumin, and TFF-3. These results support the role of major inflammatory reaction in the pathogenesis of ACLF.